Hepatitis C virus (HCV) infection is the main cause of liver diseases in the world. WHO estimates that approximately 170˜200 million people are infected with chronic HCV worldwide, which is about 3% of the global population, and there are about 3˜4 million new patients with HCV each year. While acute HCV has relatively mild clinical manifestations, it is likely to develop chronic infection. About 50-80% of patients with acute HCV will develop chronic HCV infection or even cirrhosis and hepatocellular carcinoma. Is has been reported that o those with chronic HCV infection, the risk of cirrhosis of the liver is 10-15% within 20 years. Currently, the mortality rate of hepatitis C is rated 10th among all the diseases in the world, while it is rated 5th in China.
The current standard treatment of HCV is using a combination of pegylated interferon alpha (PEG-IFN) and ribavirin (RBV). However, based on sustained virologic response (SVR), this treatment has unsatisfying clinical effects, and the cure rate for patients with genotype 1a/1b is about 50%. Further, the current treatment requires long courses. For example, the treatment of genotype 1 needs a 48 week course. Meanwhile, significant side effects (e.g., flu like symptoms, neuropsychiatric effects and anemia) may be associated with the current combination therapy, thereby resulting in the successful cure rate to be less than 10%. Thus, there is an urgent need for more effective HCV inhibitors with a novel mechanism and lower toxicity.
The hepatitis C virus is an RNA(+) virus that belongs to the family flaviviridae. The HCV genome is approximately 9.6 kilobases (kb) encoding a polypeptide of 3009-3030 amino acids. This large polypeptide is subsequently processed into 10 proteins with different functions, including the core protein—Core, the envelope proteins—E1 and E2, nonstructural proteins—NS2, NS3 (having serine protease activities, helicase activities), NS4A, NS4B, NSSA, NSSB (having polymerase activities), and a protein with unknown function—p7 (recently found likely to be an ion channel). In the protein maturation process, the cleavage of Core, E1, E2 and p7 is achieved by host signal peptidase, while the cleavage of NS2 and NS3 is catalyzed by their own cys-proteins and the mature NS3 is responsible for the cleavage processes of the remaining proteins. (Michael P. Manns et al., Nature Reviews Drug Discovery, 6, 991-1001 (2007)).
Most NS3 protease inhibitors are competitive with the substrate for the active site of the enzyme. In the beginning, some NS3 protease inhibitors are macrocyclic peptide-based mimetics, which have not been approved and are still in clinical trials. Another type of NS3 protease inhibitors is linear peptidomimetic inhibitors that possess an α-ketoamide group serine trap warhead forming a covalent but reversible complex with the enzyme.
Currently, Telaprevir and boceprevir have been approved as NS3 protease inhibitors. However, they show low in vitro activities and poor PK properties, thereby requiring high dosages. Therefore, a main goal of HCV protease inhibitors development is to develop protease inhibitors with high potency and excellent PK properties.